Regulation of expression of the DNA repair gene-O6-methylguanine-DNA methyltransferase via protein kinase C-mediated signaling

Istvan Boldogh, Chilakamarti V. Ramana, Zhenping Chen, Tapan Biswas, Tapas Hazra, Sabine Grösch, Thomas Grombacher, Sankar Mitra, Bernd Kaina

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

O6-akylguanine is the major mutagenic and cytotoxic DNA lesion induced by alkylating agents, including 2-chloroethyl-N-nitrosaurea-based antitumor drugs. This lesion is repaired by O6-methylguanine-DNA methyltransferase (MGMT), the expression of which is highly variable in both normal tissues and in tumor cells. The promoter of the human MGMT gene was found to contain two putative activator protein (AP)-1 sites. Here, we show that the level of MGMT mRNA in HeLa S3 cells was increased 3-5-fold by phorbol-12-myristate-13- acetate (TPA) and 1,2-diacyl-sn-glycerol (DAG), which are activators of protein kinase C(PKC), as well as by okaidic acid, an inhibitor of protein phosphatases. The PKC inhibitor 1-(5-isoquinoline sulfonyl)-2- methylpiperazine-HCl eliminated MGMT activation by TPA and DAG but not by OA. Prior down-regulation of PKC abolished subsequent effects of TPA or DAG. The results indicate AP-1 to be involved in regulation of MGMT expression. This hypothesis was supported by showing AP-1 binding to two target sequences of the MGMT promoter and transactivation of the MGMT promoter upon cotransfection with c-fos and c-jun in F9 cells. That TPA-mediated induction of MGMT caused increased cellular resistance to 2-chloroethyl-N-nitrosaurea suggest a therapeutic significance for PKC-mediated MGMT modulation.

Original languageEnglish (US)
Pages (from-to)3950-3956
Number of pages7
JournalCancer Research
Volume58
Issue number17
StatePublished - Sep 1 1998

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Methyltransferases
DNA Repair
Protein Kinase C
DNA
Genes
Transcription Factor AP-1
Glycerol
O-(6)-methylguanine
Protein C Inhibitor
Phosphoprotein Phosphatases
Alkylating Agents
Protein Kinase Inhibitors
HeLa Cells
Protein Binding
Antineoplastic Agents
Transcriptional Activation
Acetates
Down-Regulation
Messenger RNA
Acids

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Regulation of expression of the DNA repair gene-O6-methylguanine-DNA methyltransferase via protein kinase C-mediated signaling. / Boldogh, Istvan; Ramana, Chilakamarti V.; Chen, Zhenping; Biswas, Tapan; Hazra, Tapas; Grösch, Sabine; Grombacher, Thomas; Mitra, Sankar; Kaina, Bernd.

In: Cancer Research, Vol. 58, No. 17, 01.09.1998, p. 3950-3956.

Research output: Contribution to journalArticle

Boldogh, I, Ramana, CV, Chen, Z, Biswas, T, Hazra, T, Grösch, S, Grombacher, T, Mitra, S & Kaina, B 1998, 'Regulation of expression of the DNA repair gene-O6-methylguanine-DNA methyltransferase via protein kinase C-mediated signaling', Cancer Research, vol. 58, no. 17, pp. 3950-3956.
Boldogh, Istvan ; Ramana, Chilakamarti V. ; Chen, Zhenping ; Biswas, Tapan ; Hazra, Tapas ; Grösch, Sabine ; Grombacher, Thomas ; Mitra, Sankar ; Kaina, Bernd. / Regulation of expression of the DNA repair gene-O6-methylguanine-DNA methyltransferase via protein kinase C-mediated signaling. In: Cancer Research. 1998 ; Vol. 58, No. 17. pp. 3950-3956.
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